We have preliminary data that essentially all monozygotic twins of patients with type 1A diabetes eventually develop persistent anti-islet autoantibody expression, that a major subset, but not all such twins eventually progress to diabetes, and that a specific subgroup of siblings (HLA DR3-DQ2/DR4-DQ8 who share both HLA haplotypes with their sibling proband, but not if they share one, despite identical DR and DQ alleles) have a risk of islet autoimmunity as high as ever reported for monozygotic twins. This suggests that there is a major gene X, in linkage with DR and DQ that contributes to extreme risk of islet autoimmunity, and that subgroups of twins are likely to have different diabetes risk relative to age of progression. We propose in collaboration with TrialNet to develop a twin resource with genetically characterized and prospectively followed discordant monozygotic and dizygotic twins of patients with type 1A diabetes and non-twin siblings from the same families. Life Table projected risk of progression to expression of persistent anti-islet autoantibodies as well as diabetes will be assessed relative to known genetic polymorphisms for groups of discordant twins, and the twins will be compared to their similarly characterized non-twin siblings. We hypothesize that DR3- DQ2/DR4-DQ8 monozygotic twins, will have an extremely high risk and early time course of activating antiislet autoimmunity not different from siblings with DR3-DQ2/DR4-DQ8 who share both HLA haplotypes with their sibling proband, while dizygotic twins will not differ from HLA matched siblings of patients with a much lower risk. The specific aims of the project are: 1. Assemble and characterize the largest current series of type 1 diabetes discordant monozygotic and dizygotic twins. 2. Determine point estimate anti-islet autoantibodies. 3. Begin prospective follow-up of twins in relation to expression of islet autoimmunity and diabetes to compare with their non-twin siblings and siblings from TrialNet and DAISY. 4. Perform high density MHC+ SNP mapping in DZT and non-twin siblings from these families to identify the MHC-linked gene(s) responsible for the increased risk for islet cell autoimmunity in DR3-DQ2/DR4-DQ8 siblings who share both haplotypes with the affected family proband. We believe in the long-term it will be much easier to prevent type 1 diabetes if immunomodulatory therapies are applied prior to presence of anti-islet autoantibodies, and understanding gene/environment pathogenesis and refining genetic prediction is